[Federal Register Volume 64, Number 188 (Wednesday, September 29, 1999)]
[Rules and Regulations]
[Pages 52438-52450]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-25313]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300929; FRL-6385-6]
RIN 2070-AB78
Pymetrozine; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes a permanent tolerance for
pymetrozine [1,2,4-triazin-3(2H)-one,4,5-dihydro-6-methyl-4-[(3-
pyridinylmethylene) amino]] in or on tuberous and corm vegetables
(Subgroup 1-C), at 0.02 parts per million (ppm). Novartis Crop
Protection, Inc. of Greensboro, North Carolina 27419, requested this
tolerance under the Federal Food, Drug, and Cosmetic Act, as amended by
the Food Quality Protection Act of 1996.
DATES: This regulation is effective September 29, 1999. Objections and
requests for hearings, identified by docket control number OPP-300929,
must be received by EPA on or before November 29, 1999.
ADDRESSES: Written objections and hearing requests may be submitted by
mail, in person, or by courier. Please follow the detailed instructions
for each
[[Page 52439]]
method as provided in Unit VI. of the ``SUPPLEMENTARY INFORMATION''
section. To ensure proper receipt by EPA, your objections and hearing
requests must identify docket control number OPP-300929 in the subject
line on the first page of your response.
FOR FURTHER INFORMATION CONTACT: By mail: Dan Peacock, Registration
Division (7504C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460; telephone
number: (703) 305-5407; and e-mail address: peacock.dan@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are an agricultural
producer, food manufacturer, or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:
------------------------------------------------------------------------
Examples of
Categories NAICS Potentially
Affected Entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed in the ``FOR FURTHER INFORMATION
CONTACT'' section.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number OPP-300929. The official record
consists of the documents specifically referenced in this action, and
other information related to this action, including any information
claimed as Confidential Business Information (CBI). This official
record includes the documents that are physically located in the
docket, as well as the documents that are referenced in those
documents. The public version of the official record does not include
any information claimed as CBI. The public version of the official
record, which includes printed, paper versions of any electronic
comments submitted during an applicable comment period is available for
inspection in the Public Information and Records Integrity Branch
(PIRIB), Rm. 119, Crystal Mall 2 (CM #2), 1921 Jefferson Davis Hwy.,
Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The PIRIB telephone number is (703) 305-5805.
Persons wishing to review copies of the actual studies summarized in
this document need to file a Freedom of Information (FOI) request with
Ms. Jeralean Green, Freedom of Information Office (1105), 401 M St.,
Washington, DC 20460. Specify the MRID number of each study needed. The
FOI telephone number is (202) 260-4048.
II. Background and Statutory Findings
In the Federal Register of May 20, 1998 (63 FR 27723) (FRL-5773-2),
EPA issued a notice pursuant to section 408 of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C. 346a as amended by the Food Quality
Protection Act of 1996 (FQPA) (Public Law 104-170) announcing the
filing of a pesticide petition (PP) for tolerance by Novartis Crop
Protection, Inc. of Greensboro, NC 27419. This notice included a
summary of the petition prepared by Novartis Crop Protection, the
registrant. There were no comments received in response to the notice
of filing.
The petition requested that 40 CFR 180.556 be amended by
establishing a tolerance for residues of the insecticide pymetrozine
[1,2,4-triazin-3(2H)-one,4,5-dihydro-6-methyl-4-[(3-pyridinylmethylene)
amino]], in or on hops at 5 ppm, fruiting vegetables at 0.05 ppm, and
cucurbits and potatoes at 0.02 ppm.
Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable
certainty that no harm will result from aggregate exposure to the
pesticide chemical residue, including all anticipated dietary exposures
and all other exposures for which there is reliable information.'' This
includes exposure through drinking water and in residential settings,
but does not include occupational exposure. Section 408(b)(2)(C)
requires EPA to give special consideration to exposure of infants and
children to the pesticide chemical residue in establishing a tolerance
and to ``ensure that there is a reasonable certainty that no harm will
result to infants and children from aggregate exposure to the pesticide
chemical residue....''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. For further discussion of the
regulatory requirements of section 408 and a complete description of
the risk assessment process, see the final rule on Bifenthrin Pesticide
Tolerances (62 FR 62961, November 26, 1997) (FRL-5754-7).
III. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), EPA has reviewed the
available scientific data and other relevant information in support of
this action. EPA has sufficient data to assess the hazards of
pymetrozine and to make a determination on aggregate exposure,
consistent with section 408(b)(2), for a tolerance for residues of
pymetrozine on tuberous and corm vegetables (Subgroup 1-C), at 0.02
ppm. EPA's assessment of the exposures and risks associated with
establishing the tolerance follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. The nature of the toxic effects caused by pymetrozine are
discussed in this unit.
1. Acute toxicity. In general, technical pymetrozine has low acute
toxicity, being classified as Toxicity Category III for acute dermal
and primary eye irritation studies and Toxicity Category IV for acute
oral, acute inhalation and primary dermal studies. It is a slight
sensitizer.
2. Subchronic and chronic toxicity. This section summarizes the
results of
[[Page 52440]]
the subchronic and chronic toxicity, metabolism, and dermal penetration
studies in animals.
i. Subchronic toxicity. A subchronic feeding study in rats (MRID
No. 44024939, Guideline 82-1a), using 98% pymetrozine, exposed animals
for 3 months at dose levels of 0, 50, 500 or 5,000 ppm. These dose
levels correspond to 0, 3.42, 32.5 or 360 milligrams/kilograms/day (mg/
kg/day) in males and 0, 3.63, 33.9 or 370 mg/kg/day for females. At
5,000 ppm, body weight was decreased. Food and water consumption also
decreased. After 14 weeks, the numbers of white blood cells increased
(leucocytosis) 42% in males and 73% in females. After the 4-week
recovery period, the numbers of white blood cells were still elevated
6% in males and 35% in females. The lowest observable adverse effect
level (LOAEL) is 5,000 ppm (360 mg/kg/day) based primarily
on body weight and liver effects. The no observable adverse effect
level (NOAEL) is 500 ppm (32.5 mg/kg/day).
A subchronic feeding study in beagle dogs (MRID No. 44572201,
Guideline 82-1), using 98% pymetrozine, exposed animals for 13 weeks
(4/sex/dose) at dose levels of 0, 100, 500 or 2,500 ppm. These dose
levels corresponded to 0, 3.12, 14, or 54 mg/kg/day for either sex.
Mean relative liver weights were increased at all dose levels. At 500
ppm, both absolute (17% males and 18% females) and relative (19% males
and 17% female) liver weights were increased. In addition, skeletal
muscle myopathy (disease) in 1/4 males and 2/4 females, liver pathology
(bile duct proliferation in both sexes and hepatocyte necrosis in
females), and lymphohistocytic infiltration (several organs) increased.
At 2,500 ppm, there was one death attributable to anemia. Decreases in
red blood cell (RBC) parameters and increases in bilirubin were
observed at this dose level as well, which are also indicative of
anemia. Body weight was decreased in males (24%) and females (30%).
Additional pathology was found in the thymus (atrophy and decrease in
weight), heart (inflammation and decrease in weight), testis (decrease
in spermatogenesis and weight) and uterus (atrophy). The LOAEL is 500
ppm (14 mg/kg/day) based on liver effects, skeletal muscle
atrophy, liver pathology and lymphohistocytic infiltration. The NOAEL
is 100 ppm (3.12 mg/kg/day). Slight liver weight changes at
100 ppm were not considered in the LOAEL.
A subchronic feeding study in the mouse (MRID No. 44024938,
Guideline 82-1c), using 98% pymetrozine and designed to determine the
dose levels for the definitive carcinogenicity study, exposed mice for
3 months at 0, 1,000, 3,000 or 7,000 ppm. Mean relative liver weights
were increased in the low (10.5%), mid (26%) and high (57%) dose males
and in the low (12%, not significant), mid (33%) and high (54%) dose
females. The liver also showed increases in centrilobular hypertrophy
of hepatocytes (swelling of liver cells) with a dose response of 0, 3,
7 and 10 in males and 0, 2, 5, and 10 in females for four dose levels.
The liver also was indicated as having ``slight centrilobular
perivascular-like aggregates of lymphocytes'' in all dose groups except
the control and demonstrated a marked dose response with treatment.
Necrosis of the liver was also increased in a dose related manner.
Relative spleen weight was also increased at 3,000 ppm (21% in males
and 19% in females) and 7,000 ppm (53% in males and 16% in females) and
was accompanied by splenic extramedullary hematopoiesis above
background. Thus, the liver and blood forming system were indicated as
target organs for pymetrozine. Body weight at termination was decreased
(17%) in males in the high dose group but was actually slightly
increased (7%, not significant) in females.
A 28-day dermal toxicity study in the rat (MRID No. 44024942,
Guideline No. 82-2), using 98% pymetrozine, exposed animals at 0, 10,
100 or 1,000 mg/kg/day for 6 hours/day, 5 days/week for 4 weeks. The
agent was suspended in distilled water and was applied directly to
clipped skin using an occlusive dressing. No treatment-related clinical
signs or signs of local irritation were observed. Hematology and
clinical biochemistry performed on the test animals revealed no
treatment-related effects. Macroscopic and microscopic examination of
internal organs and the application site revealed no treatment-related
findings. The NOAEL for both systemic effects and dermal irritation is
1,000 mg/kg/day, the highest dose tested (HDT). The LOAEL is greater
than 1,000 mg/kg/day.
ii. Chronic toxicity. A chronic feeding study in beagle dogs (MRID
No. 44024943, Guideline 83-1), using 98% pymetrozine, exposed animals
for 12 months at 0, 20, 200 and 1,000 ppm (corresponding to
approximately 0, 0.57, 5.33 or 27.8 mg/kg/day in both sexes). At 200
ppm, there were increases in mean absolute (11%) and relative (17%)
liver weights in males. At 1,000 ppm, mean absolute (6%) and relative
(11%) liver weights were higher in both males and females (absolute
(18%) and relative (6%)). In addition, in males, there was also
increased inflammatory cell infiltration in the liver (4/6 vs 2/6 in
the control group); and myopathy (2/6 vs 0/6 in the control group) in
the small and large intestine. Anemia was apparent in two females. The
LOAEL is 1,000 ppm (27.8 mg/kg/day), based primarily on myopathy
(muscle disease) and presence of anemia (reduction in red blood cells).
The NOAEL is 200 ppm (5.33 mg/kg/day). Similar findings in the dog
subchronic study (MRID No. 44572201) regarding anemia and liver
pathology support the conclusions of this study.
An 18-month definitive carcinogenicity study in mice (MRID No.
44024944, OPPTS No. 870.4200 or Guideline No. 83-2), using 98%
pymetrozine, exposed animals (50/sex/dose group) for 18 months at 0,
10, 100, 2,000 or 5,000 ppm. These dose levels correspond to
approximately 0, 1.2, 12, 250 and 675 mg/kg/day pymetrozine in either
sex. At 2,000 ppm, relative liver weight increased in males (36%) and
females (17%), with hepatocyte hypertrophy occurring in most affected
animals. Hemosiderosis (increase in storage of insoluble form of iron)
and extramedullary hematopoiesis (red blood cell formation) were also
increased. Relative liver weight was increased by 78% in males and by
62% in females. The systemic LOAEL was 2,000 ppm (250 mg/
kg/day) based on increases in liver weight as well as hepatocyte
hypertrophy and hemosiderosis. The NOAEL is 100 ppm (12 mg/
kg/day). Liver tumors were associated with the higher doses (2,000 and
5,000 ppm) of pymetrozine exposure with 5, 5, 5, 9 and 23 (males) and
0, 0, 0, 0 and 4 (females) hepatocellular carcinomas and 4, 5, 5, 1 and
14 hepatocellular ``benign adenoma'' in females for the control, 10,
100, 2,000 and 5,000 ppm dose groups, respectively. Males did not show
increases in adenomas. The increases in liver weight and presence of
hypertrophy and hematopoieses may imply that the high dose was
excessive for meaningful carcinogenicity evaluation.
A combined chronic feeding/carcinogenicity study in the rat (MRID
No. 44024951, Guideline No. 83-5, using 98% pymetrozine, exposed
animals for 12 and 24 months. Five groups of 80/sex were dosed at 0,
10, 100, 1,000 or 3,000 ppm in the diet, corresponding to 0, 0.377,
3.76, 38.52 or 123.4 mg/kg/day for males and 0, 0.454, 4.48, 46.26 or
148.3 mg/kg/day for females. Ten/sex/group were sacrificed at 12
months. Fifty/sex/group were reserved for carcinogenicity assessment
after dosing for a scheduled 24 months. For the control, 10, 100, 1,000
and 3,000 ppm dietary groups (based on 60/sex),
[[Page 52441]]
hepatocellular hypertrophy was present with the following total
incidence: for males, 0, 1, 5, 22 and 37 and for females, 2, 1, 0, 12
and 40. At the 1 year interim sacrifice, the incidence in males was 0,
0, 4, 10 and 10 (out of 10/group). Thus indicating in males that the
100 ppm dose is an effect level for induction of hepatocellular
hypertrophy. At 1,000 ppm, body weight and gain were reduced (i.e., at
4 weeks males 6% and females 12%, p < 0.05="" less="" gain)="" and="" relative="" liver="" (26%,="" p="">< 0.05),="" spleen="" (24%,="" p="">< 0.05)="" and="" kidney="" (14%,="" not="" significant)="" weights="" were="" increased="" in="" males="" at="" week="" 53.="" at="" 3,000="" ppm,="" the="" magnitude="" of="" the="" effects="" at="" 1,000="" ppm="" was="" increased="" and,="" in="" addition,="" female="" liver,="" spleen,="" kidney,="" brain="" and="" ovary="" as="" well="" as="" male="" brain="" and="" testis="" relative="" weights="" increased.="" the="" uterus="" showed="" increased="" dilation.="" the="" systemic="" loael="" is="" 100="" ppm="" (3.76="" mg/kg/day)="" based="" on="" hepatocellular="" hypertrophy="" in="" males.="" the="" noael="" is="" 10="" ppm="" (0.377="" mg/kg/day).="" in="" females,="" the="" systemic="" loael="" is="" 1,000="" ppm="" (46.26="" mg/kg/day)="" and="" the="" noael="" is="" 100="" ppm="" (4.48="" mg/kg/day)="" based="" on="" hepatocellular="" hypertrophy="" and="" reduced="" body="" weight="" and="" body="" weight="" gain.="" this="" study="" was="" considered="" positive="" for="" induction="" of="" liver="" tumors="" (benign="" hepatoma)="" at="" 1,000="" and="" 3,000="" ppm="" in="" females.="" the="" presence="" of="" hepatocellular="" hypertrophy="" at="" 1,000="" and="" 3,000="" ppm="" and="" decreased="" body="" weight="" at="" 3,000="" ppm="" may="" provide="" a="" basis="" for="" determining="" that="" the="" dose="" levels="" associated="" with="" liver="" tumors="" were="" excessive.="" 3.="" neurotoxicity.="" an="" acute="" neurotoxicity="" study="" in="" the="" rat="" (mrid="" no.="" 44411317,="" guideline="" 81-8)="" exposed="" animals="" in="" groups="" of="" 10/sex="" at="" dose="" levels="" of="" 0,="" 125,="" 500="" or="" 2,000="" mg/kg/day.="" the="" loael="" is="" 125="" mg/kg="" based="" on="" decreases="" in="" body="" temperature,="" function="" observation="" battery="" (fob)="" changes,="" and="" decreased="" motor="" activity="" (in="" males)="" related="" to="" decreased="" activity.="" the="" noael="" is="">< 125="" mg/kg/day.="" a="" 13-week="" subchronic="" neurotoxicity="" study="" in="" the="" rat="" (mrid="" no.="" 44411318,="" guideline="" no.="" 82-7)="" exposed="" groups="" of="" 10="" animals/sex="" at="" dose="" levels="" of="" 0,="" 500,="" 1,000="" or="" 3,000="" ppm.="" systemic="" effects="" of="" treatment="" were="" evident="" at="" 3,000="" ppm="" only="" and="" were="" limited="" to="" decreased="" body="" weight="" gain="" (10-18%="" in="" males="" and="" 7-10%="" in="" females).="" at="" this="" dose,="" indications="" of="" neurotoxicity="" were="" limited="" to="" stereotypy="" (repetition="" of="" senseless="" movements)="" in="" males="" (3/10="" affected="" at="" week="" 4="" and="" 1/10="" affected="" at="" weeks="" 8="" and="" 13).="" there="" were="" also="" indications="" of="" tiptoe="" gait="" or="" walking="" on="" toes="" in="" females="" at="" all="" intervals="" but="" only="" statistically="" significant="" at="" week="" 13.="" the="" loael="" is="" 3,000="" ppm="" (equivalent="" to="" a="" mean="" of="" 201="" mg/kg/day="" for="" males="" and="" 224="" mg/kg/day="" in="" females)="" based="" on="" decreased="" weight="" and="" stereotypy="" in="" males="" as="" well="" as="" tiptoe="" gait="" in="" females.="" the="" noael="" is="" 1,000="" ppm="" (equivalent="" to="" a="" mean="" of="" 68="" mg/kg/day="" in="" males="" and="" 81="" mg/kg/day="" for="" females).="" 4.="" developmental="" toxicity.="" a="" developmental="" study="" in="" the="" rat="" (mrid="" no.="" 44024948,="" oppts="" no.="" 870.3700="" or="" guideline="" no.="" 83-3a),="" using="" 98%="" pymetrozine,="" exposed="" groups="" of="" 24="" animals="" in="" a="" 0.5%="" w/w="" aqueous="" solution="" of="" sodium="" carboxymethylcellulose="" at="" either="" 0,="" 30,="" 100="" or="" 300="" mg/kg/day="" by="" oral="" gavage="" from="" gestation="" days="" 6="" through="" 15,="" inclusive.="" maternal="" systemic="" toxicity="" was="" seen="" as="" reduced="" body="" weights="" gains="" in="" the="" 100="" and="" 300="" mg/kg/day="" dose="" groups="" during="" the="" dosing="" period="" (gestation="" days="" 6-16),="" the="" dosing="" period="" plus="" post-dosing="" period="" (gestation="" days="" 6-21="" for="" 300="" mg/kg/day)="" and="" the="" corrected="" body="" weight="" gain="" for="" the="" dosing="" period="" plus="" post-dosing="" period="" (statistically="" significant="" for="" both="" 100="" and="" 300="" mg/kg/day).="" there="" was="" reduced="" food="" consumption="" in="" the="" same="" groups="" during="" the="" dosing="" period.="" the="" maternal="" toxicity="" noael="" was="" 30="" mg/kg/day="" and="" the="" maternal="" toxicity="" loael="" was="" 100="" mg/kg/day="" based="" on="" reduced="" body="" weight="" gains="" and="" food="" consumption.="" developmental="" toxicity="" was="" observed="" as="" an="" increase="" in="" skeletal="" observations="" at="" 300="" mg/kg/day="" including="" dumbbell-shaped="" thoracic="" vertebral="" centers,="" absent="" ossification="" of="" metatarsal="" #1,="" shortened="" rib="" #13,="" absent="" ossification="" of="" the="" proximal="" phalanx="" of="" anterior="" digit="" #5,="" absent="" ossification="" of="" the="" proximal="" phalanx="" of="" posterior="" digit="" #2,="" #3="" and="" #4,="" and="" absent="" and="" poor="" ossification="" of="" the="" proximal="" phalanx="" of="" posterior="" digit="" #5.="" the="" developmental="" toxicity="" noael="" was="" 100="" mg/kg/day="" and="" the="" developmental="" toxicity="" loael="" was="" 300="" mg/kg/day="" based="" on="" increased="" incidence="" of="" skeletal="" anomalies.="" a="" developmental="" study="" in="" the="" rabbit="" (mrid="" no.="" 44024949,="" oppts="" no.="" 870.3700="" or="" guideline="" no.="" 83-3b),="" using="" 98%="" pymetrozine,="" exposed="" groups="" of="" 20="" animals="" in="" a="" 0.5%="" w/w="" aqueous="" solution="" of="" sodium="" carboxymethylcellulose="" at="" either="" 0,="" 10,="" 75="" or="" 125="" mg/kg/day="" by="" oral="" gavage="" from="" gestation="" days="" 7="" through="" 19,="" inclusive.="" maternal="" systemic="" toxicity="" was="" seen="" as="" reduced="" body="" weight="" gains="" in="" the="" 75="" and="" 125="" mg/kg/="" day="" dose="" groups.="" there="" was="" also="" reduced="" food="" consumption="" in="" the="" mid="" and="" high="" dose="" groups.="" there="" was="" reduced="" food="" efficiency="" noted="" in="" the="" mid="" and="" high="" dose="" groups="" during="" all="" periods="" except="" for="" predosing="" (gestation="" days="" 0-7).="" at="" 125="" mg/kg/day,="" two="" dams="" died="" and="" one="" aborted="" the="" entire="" litter="" during="" the="" dosing="" period.="" (note:="" these="" observations="" were="" also="" noted="" in="" the="" rangefinding="" study).="" the="" maternal="" toxicity="" noael="" was="" 10="" mg/kg/day="" and="" the="" maternal="" toxicity="" loael="" was="" 75="" mg/kg/day="" based="" on="" reduced="" body="" weight="" gains="" and="" food="" consumption/efficiency.="" developmental="" toxicity="" was="" observed="" as="" an="" increase="" in="" additional="" 13th="" ribs="" in="" the="" 75="" and="" 125="" mg/kg/day="" dose="" groups="" and="" an="" increase="" in="" skeletal="" observations="" at="" 125="" mg/kg/day="" seen="" as="" fused="" sternebrae="" #2="" &="" 3,="" #3="" &="" 4="" and="" #4="" &="" 5,="" additional="" caudal="" vertebral="" centers,="" poor="" ossification="" of="" metacarpal="" #1,="" poor="" ossification="" of="" the="" talus="" of="" the="" hind="" limb,="" and="" poor="" ossification="" of="" the="" anterior="" digit="" #5="" medial="" phalanx.="" also,="" there="" was="" reduced="" litter="" size,="" increased="" resorptions="" and="" increased="" post-implantation="" loss="" in="" the="" 125="" mg/kg/day="" dose="" group.="" the="" developmental="" toxicity="" noael="" was="" 10="" mg/kg/day="" and="" the="" developmental="" toxicity="" loael="" was="" 75="" mg/kg/day="" based="" on="" increased="" incidence="" of="" skeletal="" anomalies.="" 5.="" reproductive="" toxicity.="" a="" multigeneration="" reproduction="" study="" in="" the="" rat="" (mrid="" no.="" 44024950,="" oppts="" no.="" 870.3800="" or="" guideline="" no.="" 83-4),="" using="" 98%="" pymetrozine,="" exposed="" groups="" of="" 30="" animals="" at="" 0,="" 20,="" 200="" or="" 2,000="" ppm="" in="" the="" diet="" for="" two="" successive="" generations.="" parental="" systemic="" toxicity="" included="" minimal="" hepatocellular="" hypertrophy="" in="" 5/30="" 200="" ppm="" f0="" males,="" 27/30="" 2,000="" ppm="" f0="" males="" and="" 2/30="" 2,000="" ppm="" f0="" females,="" in="" addition="" to="" minimal="" to="" moderate="" hyperplasia="" of="" lymphatic="" follicles="" of="" splenic="" white="" pulp="" in="" 25/30="" 2,000="" ppm="" f0="" females.="" the="" f1="" animals="" had="" minimal="" hepatocellular="" hypertrophy="" in="" 2/30="" 200="" ppm="" males,="" 26/30="" 2,000="" ppm="" males="" and="" 10/30="" 2,000="" ppm="" females,="" in="" addition="" to="" minimal="" to="" moderate="" hypertrophy="" of="" the="" basophilic="" cells="" in="" the="" adenohypophysis="" in="" 17/30="" 2,000="" ppm="" males,="" compared="" to="" 7/30,="" 8/30,="" 7/30="" for="" the="" control,="" 20="" ppm="" and="" 200="" ppm="" groups,="" respectively.="" further,="" there="" were="" increased="" absolute="" and="" relative="" spleen="" and="" liver="" weights="" in="" the="" f0="" and="" f1="" 2000="" ppm="" animals="" plus="" decreased="" absolute="" and="" relative="" thymus="" weights="" in="" the="" 2,000="" ppm="" f1="" animals.="" the="" investigators="" concluded="" that="" the="" liver="" was="" the="" target="" organ="" in="" both="" sexes="" in="" both="" generations;="" in="" addition,="" the="" spleen="" was="" the="" target="" organ="" in="" f0="" females,="" whereas="" the="" pituitary="" gland="" was="" affected="" in="" f1="" males.="" systemic="" toxicity="" to="" the="" paternal="" animals="" included="" reduced="" body="" weights,="" reduced="" body="" weight="" gains,="" and="" reduced="" food="" consumption.="" systemic="" toxicity="" to="" f1="" groups,="" included="" reduced="" body="" weights,="" reduced="" body="" weight="" gains,="" and="" reduced="" food="" consumption.="" the="" parental="" (paternal/="" [[page="" 52442]]="" maternal)="" systemic="" toxicity="" noael="" was="" 20="" ppm="" (1.4-1.7="" mg/kg/day="" for="" males="" and="" 1.6-1.8="" mg/kg/day="" for="" females)="" and="" the="" parental="" (paternal/="" maternal)="" systemic="" toxicity="" loael="200" ppm="" (13.9-17.0="" mg/kg/day="" for="" males="" and="" 16.0-18.1="" mg/kg/day="" for="" females)="" based="" on="" liver="" effects="" in="" the="" f0="" and="" f1="" males.="" the="" reproductive="" toxicity="" noael="" is="" equal="" to="" or="" greater="" than="" 2,000="" ppm="" (136.9-179.0="" mg/kg/day="" for="" males="" and="" 151.6-186.5="" mg/kg/day="" for="" females)="" and="" the="" reproductive="" toxicity="" loael="" is="" greater="" than="" 2,000="" ppm="" (136.9-179.0="" mg/kg/day="" for="" males="" and="" 151.6-186.5="" mg/kg/="" day="" for="" females),="" since="" no="" reproductive="" effects="" were="" noted="" at="" the="" highest="" dose="" tested.="" the="" offspring="" systemic/developmental="" toxicity="" noael="" was="" 200="" ppm="" (13.9-17.0="" mg/kg/day="" for="" males="" and="" 16.0-18.1="" mg/kg/="" day="" for="" females)="" and="" the="" offspring="" systemic/developmental="" toxicity="" loael="" was="" 2,000="" ppm="" (136.9-179.0="" mg/kg/day="" for="" males="" and="" 151.6-186.5="" mg/kg/day="" for="" females)="" based="" on="" decreased="" pup="" weight="" and="" delay="" in="" eye="" opening="" in="" both="" f1="" and="" f2="" litters.="" 6.="" mutagenicity.="" a="" reverse="" gene="" mutation="" assay="" in="" bacteria="" (mrid="" no.="" 44024952,="" guideline="" no.="" 84-2),="" using="" 98%="" pymetrozine,="" exposed="" cultures="" of="" salmonella="" typhimurium="" histidine-deficient="" (his-)="" mutant="" strains="" ta98,="" ta100,="" ta1535="" and="" ta1537,="" and="" the="" escherichia="" coli="" tryptophan-deficient="" (try-)="" strain="" wp2="" uvra="" in="" triplicate="" to="" five="" concentrations="" ranging="" from="" 312.5="" to="" 5,000="">g/plate, in the
presence or absence of a mammalian metabolic activation system (S9 plus
cofactors) derived from the microsomal fraction (S9) of livers from
adult male RAI rats pretreated with Aroclor 1254. In neither the
initial nor confirmatory trial were any increased incidences of his+ or
try+ colonies found, compared to solvent control values, in contrast to
the strongly positive responses in all mutagen-treated cultures.
Therefore, in this in vitro test, pymetrozine is considered negative
for reverse gene mutation in these strains of bacteria.
A mammalian cell forward gene mutation assay in cultures of Chinese
hamster lung (V79) cells (MRID No. 44024954, Guideline No. 84-2), using
98% pymetrozine, exposed cultures in duplicate at four concentrations
ranging from 5.21 to 333.3 g/mL, for 21 hours in the absence
of a mammalian metabolic activation system or for 5 hours followed by
16 hours in test article-free tissue culture medium in the presence of
activation provided by the microsomal fraction (S9) of livers from
adult male RAI rats pretreated with Aroclor 1254. Cultures were
negative for the induction of forward gene mutation at the HGPRT locus
in this test system.
A mammalian cell cytogenetics (chromosome aberrations) assay in
Chinese hamster ovary (CHO) cells (MRID No. 44024953, Guideline No. 84-
2), using 98% pymetrozine, exposed cultures at eight concentrations
ranging from 2.58 to 330 g/mL for 18 hours in the absence of
mammalian metabolic activation or for 3 hours in the presence of S9
activation (S9 microsomal fraction of livers from adult male rats
pretreated with Aroclor 1254, plus co-factors) followed by recovery in
treatment-free medium for 15 hours. Cultures were not clastogenic; at
none of the concentrations nor harvest times was the incidence of
structural chromosome aberrations reported to exceed either the
concurrent or historical control values.
A micronucleus test in mice (MRID No. 44024955, Guideline 84-2),
using 98% pymetrozine, exposed groups of 8 animals/sex orally by gavage
in two series of trials: (1) Three groups at a single maximum tolerated
dose (MTD) of 4,000 mg/kg and (2) three groups at single doses of
1,000, 2,000 and 4,000. No statistically significant increases over
controls were found in MPCE in any group at any sacrifice time. In
addition, no effects of treatment were calculated in PCE/NCE ratios at
any time or dose point. CPA-treated positive control animals responded
with highly significant increased MPCE.
An unscheduled DNA synthesis assay in primary rat hepatocyte cells
(MRID No. 44024956, Guideline No. 84-2), using 98% pymetrozine, exposed
cultures in two trials in dimethylsulfoxide (DMSO) at six
concentrations ranging from 2.78 to 300 g/mL for 16-18 hours
in the presence of tritiated thymidine. In this genotoxicity
mutagenicity test, there was no evidence that the treatment induced
unscheduled DNA synthesis, as determined by radioactive tracer
procedures (nuclear silver grain counts).
7. Absorption, distribution and metabolism. A metabolism study in
rats (MRID No. 44024957, Guideline 85-1), using radiolabeled
pymetrozine, exposed animals orally or intravenously in groups of 5
animals/sex to evaluate absorption and excretion. Within the first 24
hours post-dosing, the urine from all orally-dosed groups contained
from 52.0% to 73.5% of the administered radioactivity. The intravenous
treated rats also had comparable 24-hour urine levels which were 63.6%
and 68.3% of the administered dose in males and females, respectively.
At study termination (7 days post-dosing), the recovered radioactivity
in urine (56.3-80.3%), expired air (0.2-1.4%), tissues (0.3-3.8%),
feces (15.4-38.9%), and cage washes (0.2-0.7%) accounted for a total
recovery of 91-100.7% of the administered dose in all groups. The
relatively high urinary level of unchanged test material suggests
metabolic saturation at the high dose of 100 mg/kg.
A metabolism study in female rats (MRID No. 44517720, OPPTS No.
870.7485, Guideline No. 85-1), using radiolabled pymetrozine, exposed
animals orally to a single low dose (0.5 mg/kg) or a high dose (100 mg/
kg). Irrespective of the label site, the time to maximum blood
concentrations (tmax) were attained at 1 hour (0.1 ppm for both labels)
and at 8 hours (41 ppm for triazine and 52 ppm for pyridine) following
low and high oral dosing, respectively. While the peak blood levels
were dependent on the dose but independent of the labeling site, the
pyridine label was more persistent than the triazine label. At all time
points and irrespective of the dose or labeling site, tissue residue
levels (ppm) were highest in the kidneys and liver. For the low/high
doses, the peak kidney levels were 0.6/75 ppm (triazine) and 0.6/101
ppm (pyridine), while the peak liver levels were 0.4/59 ppm (triazine)
and 0.5/176 ppm (pyridine). Of all tissues (with the exception of the
GI tract), the skeletal muscle had the highest percent of the
administered dose (both labels) accounting for 7 to 8% of the low dose
at 1 hour and for 19 to 21% of the high dose at 8 hours. The calculated
half life times (t\1/2\) for the triazine residue depletion from all
the tissues ranged from 2.9 to 4.8 hours (low dose) and from 1.9 to 3.5
hours (high dose) and for the pyridine radiolabel depletion, from 31.7
to 110.3 hours (low dose) and from 2.5 to 13.9 hours (high dose).
Absorption was lower at the high dose representing nearly 82% of
the administered dose for both radiolabels. Irrespective of the
labeling site, the biliary excretion was higher at the low dose than at
the high dose. The total 48-hour excretion, including cage wash, was
higher at both dose levels for the triazine label (low dose/ high dose:
103%/95%) than the pyridine label (low dose/high dose: 85%/81%). These
results confirm other findings (above) that of the two moieties,
pyridine is more persistent than triazine.
8. Dermal absorption. A dermal absorption study in male rats (MRID
No. 44024958, Guideline No. 85-3), using 98.1-99.5% radiolabeled
pymetrozine, exposed 24 male animals in 0.5% carboxy-methyl cellulose
aqueous suspension at dose levels of 0.084, 0.503, or 4.69 mg/rat
(0.0067, 0.0402, or
[[Page 52443]]
0.375 mg/cm2). After blood collection, four rats/dose were
killed for assessment of dermal absorption after 0.5, 1, 2, 4, 10, and
24 hours of exposure. Urine and feces were also collected at the time
of killing. After 24 hours of exposure, dermal absorption of CGA-215944
was minimal (0.05%, 0.01%, and <0.005% for="" the="" low,="" mid,="" and="" high="" dose="" groups,="" respectively).="" for="" all="" dose="" groups,="" the="" majority="" of="" the="" dose="" (81.4-100.0%)="" was="" not="" absorbed="" and="" was="" recovered="" in="" the="" skin="" wash.="" for="" all="" dose="" groups,="" adsorption="" to="" skin="" from="" the="" test="" site="" (0.18-8.84%)="" accounted="" for="" the="" next="" largest="" proportion="" of="" the="" dose="" and="" only="" trace="" amounts="">0.05%) of radioactivity were excreted in the urine
and feces. Within each dose group, radioactivity remaining in/on the
skin after washing did not seem to increase with the duration of
exposure; likewise, absorption (measured as amount excreted plus amount
retained in the body) did not seem to increase over time.
9. Special studies. A cell proliferation study in young adult male
mice (MRID No. 44024923), using 97.4% pymetrozine, exposed 15 groups of
animals in a basal diet as follows: (i) Two groups at dietary
concentrations of 0 and 5,000 ppm for 4 days (corresponding to intakes
of 0 and 891.6 mg/kg/day); (ii) six groups at concentrations of 0, 10,
100, 500, 2,000 and 5,000 ppm for 14 days (intakes of 0, 1.6, 15.6,
83.9, 323.4 and 876.7 mg/kg/day); (iii) six groups at concentrations of
0, 10, 100, 500, 2,000 and 5,000 ppm for 42 days (intakes of 0, 1.6,
13.3, 70.7, 299.9 and 767.1 mg/kg/day); and (iv) a single group at a
concentration of 5,000 ppm for 14 days (intake of 1,006 mg/kg/day),
followed by a recovery period of 28 days, in order to test for
reversibility of any treatment-related changes. No clinical signs of
toxicity were observed in any group throughout the treatment and/or
recovery periods. Absolute and relative liver weights were slightly
increased at 4-days treatment with 5,000 ppm, but significantly so
after 14 and 42 days at this high concentration as well as 2,000 ppm,
indicating hypertrophy. Absolute and relative liver weights returned to
control levels in the 14-day treatment/28 day recovery animals.
Significant decreases in the mean number of total nuclei were recorded
at 2,000 ppm (16% ) and at 5,000 ppm (17-18% )
after 14 and 42 days. These findings, in conjunction with evidence that
the enlarged hepatocytes at 5,000 ppm (14 and 42 days) often contained
vacuoles, slight focal single cell necrosis and PCNA+ inflammatory cell
infiltration that occurred at a higher frequency in the livers of mice
at 5,000 ppm (14 and 42 days) than in the vehicle control liver
samples, indicate that the test material induced a cytotoxic effect on
the target organ. Immunohistochemical staining of liver sections
revealed significant increases in PCNA values in both 2,000 and 5,000
ppm groups at all time points. Cell proliferation effects were
reversible in animals treated at 5,000 ppm for 14 days followed by a
28-day recovery. Thus, these results show that the observed
hepatomegaly in mouse liver at the 2,000 and 5,000 ppm treatment levels
was the combined result of hypertrophy and hyperplasia. Accordingly,
the LOAEL is 2,000 ppm, based on increased liver weight, reduced total
hepatocytes, microscopic evidence of necrosis and significant increases
in the LI for cell proliferation; the NOAEL is 500 ppm level. Overall,
the findings of this study offer support for the hypothesis that the
increased incidence of hepatocellular carcinomas in a previous 18-month
carcinogenicity study in mice was due to (reversible) replicative DNA
synthesis, with a threshold effect at a NOAEL = 500 ppm.
A special study in male rats (MRID No. 44517723), using 97.8%
pymetrozine and conducted to evaluate possible mechanisms for liver
tumor formulation, exposed 6 groups of 16 animals in diets containing
0, 25, 50, 100 or 1,000 ppm for 18 weeks. Assessments were limited to
cage side observations for clinical signs, body weight and food plus
water consumption. Pathology was limited to organ assessment of the
liver and thyroid for weight and macroscopic and histopathological
lesions but also included a special assessment for the
immunohistological evaluation of the glutathione S-transferase
placental from positive hepatocyte (GST-P) foci, a foci induced by the
presence of the initiators. Pymetrozine produced its expected increase
in liver and thyroid weight but did not increase the GST-P foci thus
was not considered positive for a promotional effect of proliferative
lesions in the liver. Pymetrozine was associated with an increase (p < 0.05)="" in="" follicular="" cell="" adenomas="" only="" in="" the="" 100="" ppm="" dose="" group="" but="" there="" was="" no="" associated="" increase="" in="" thyroid="" hyperplasia="" or="" similar="" effect="" at="" 1,000="" ppm.="" overall,="" it="" could="" not="" be="" concluded="" that="" pymetrozine="" resulted="" in="" promotion="" of="" proliferative="" lesions="" in="" either="" the="" rat="" liver="" or="" thyroid="" at="" dose="" levels="" up="" to="" and="" including="" 1,000="" ppm.="" b.="" toxicological="" endpoints="" 1.="" acute="" dietary="" toxicity="" --="" i.="" females="" 13="" years="" and="" older.="" the="" agency="" selected="" a="" noael="" of="" 10="" mg/kg/day="" from="" the="" rabbit="" developmental="" study="" (mrid="" no.="" 44024949)="" for="" the="" acute="" dietary="" endpoint,="" based="" on="" reduced="" body="" weight="" gains="" and="" reduced="" food="" consumption="" and="" efficiency="" in="" mothers="" and="" an="" increased="" incidence="" of="" skeletal="" anomalies="" in="" pups="" at="" the="" loael="" of="" 75="" mg/kg/day.="" the="" selection="" of="" the="" rabbit="" developmental="" toxicity="" study="" is="" comparable="" to="" the="" rat="" developmental="" toxicity="" study,="" which="" had="" a="" maternal="" noael="" and="" loael="" of="" 30="" and="" 100="" mg/kg/day,="" respectively.="" ii.="" acute="" dietary="" toxicity="" (general="" population="" and="" infants="" and="" children).="" the="" agency="" selected="" the="" loael="" of="" 125="" mg/kg="" (lowest="" dose="" tested)="" from="" the="" acute="" rat="" neurotoxicity="" study="" (mrid="" no.="" 44411317)="" for="" the="" acute="" dietary="" endpoint="" for="" the="" general="" population,="" including="" infants="" and="" children,="" based="" on="" decreased="" body="" temperature,="" decreased="" motor="" activity,="" and="" fob="" parameters="" associated="" with="" decreased="" activity.="" 2.="" short-="" and="" intermediate-term="" toxicity.="" for="" dermal="" exposure,="" the="" agency="" selected="" a="" noael="" of="" 1,000="" mg/kg/day="" from="" a="" 28-day="" dermal="" toxicity="" in="" the="" rat="" (mrid="" no.="" 44024942)="" because="" there="" were="" no="" effects="" at="" the="" highest="" dose="" tested.="" based="" on="" these="" results,="" the="" agency="" did="" not="" perform="" a="" short-="" or="" intermediate-term="" dermal="" risk="" assessments.="" for="" short-term="" (1-7="" days)="" inhalation="" exposure,="" the="" agency="" selected="" (in="" the="" absence="" of="" an="" inhalation="" study)="" an="" oral="" noael="" of="" 10="" mg/kg/day="" from="" a="" developmental="" study="" in="" the="" rabbit="" (mrid="" no.="" 44024949),="" based="" on="" reduced="" body="" weight="" gains="" and="" food="" consumption="" and="" efficiency="" in="" mothers="" and="" an="" increased="" incidence="" of="" skeletal="" anomalies="" in="" pups="" at="" the="" loael="" of="" 75="" mg/kg/day.="" for="" intermediate="" (7="" days="" to="" several="" months)="" inhalation="" exposure,="" the="" agency="" selected="" (in="" the="" absence="" of="" an="" inhalation="" study)="" an="" oral="" noael="" of="" 10="" ppm="" (0.377="" mg/kg/day)="" from="" a="" chronic="" feeding="" study="" in="" the="" rat="" (mrid="" no.="" 44024951),="" based="" on="" hepatocellular="" (liver)="" hypertrophy="" in="" males="" at="" an="" loael="" of="" 100="" ppm="" (3.76="" mg/kg/day).="" 3.="" chronic="" toxicity.="" for="" chronic="" dietary="" exposure,="" epa="" has="" selected="" an="" oral="" noael="" of="" 10="" ppm="" (0.377="" mg/kg/day)="" from="" a="" chronic="" feeding="" study="" in="" the="" rat="" (mrid="" no.="" 44024951),="" based="" on="" hepatocellular="" (liver)="" hypertrophy="" in="" males="" at="" an="" loael="" of="" 100="" ppm="" (3.76="" mg/kg/day).="" 4.="" carcinogenicity.="" epa="" has="" classified="" pymetrozine="" as="" a``likely="" human="" carcinogen''="" and="" recommended="" that="" quantification="" of="" risk="" be="" estimated="" for="" combined="" (benign="" hepatomas="" and/or="" carcinomas)="" liver="" tumors="" in="" male="" and="" [[page="" 52444]]="" female="" mice="" and="" female="" rats.="" epa="" selected="" a="" unit="" risk,="" q1*,="" of="" 2.05="" x="">1 (mg/kg/day)-1 for quantification of the
cancer risk and has determined the cancer dose to be 0.0000049 mg/kg/
day. The Agency reviewed ``mechanism of action'' studies, but these
were insufficient to affect the classification of carcinogenicity.
5. Dermal penetration. The dermal penetration study (MRID No.
44024958) in rats indicated that the amount of pymetrozine capable of
penetrating the skin is very small (no more than 0.28%). However,
because the EPA concluded that the study may have underestimated the
actual amount of dermal penetration, the Agency has used a dermal
penetration value of 1% in risk assessments.
6. Long-term (several months to life-time) dermal and inhalation
endpoints. The current use pattern does not indicate a concern for
long-term dermal or inhalation exposure potential.
7. Safety (uncertainty) factors, including FQPA safety factor. The
Agency will use the above NOAELs and LOAELs levels to assess the risks
of using pymetrozine to the general population and certain subgroups of
the general population. However, the Agency first modifies these values
numerically, downward, by dividing the NOAEL dose by one or more safety
factors. These safety factors may represent the uncertainty of the
individual variation among animals for all studies (10 fold safety or
uncertainty factor), of using animal studies to assess human risk for
all studies (10 fold safety factor); and of using a LOAEL in place of a
NOAEL to estimate the risk (3 fold safety factor).
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for prenatal and postnatal toxicity and
the completeness of the data base unless EPA determines that a
different margin of safety will be safe for infants and children. As
noted, EPA has added an additional three-fold factor to the acute
dietary risk assessment for infants and children due to the lack of a
NOAEL in the critical study. An additional 3-fold factor is also needed
due to the uncertainty resulting from the data gap for the
developmental neurotoxicity study in rats. This latter safety factor is
applicable to the following subgroup populations: Females 13-50;
infants, children (1-6 years), and children (7-12 years) for all risk
assessment scenarios for acute and chronic dietary and residential
scenarios. No greater additional factor is needed because:
There was no evidence of developmental effects being
produced in fetuses at lower doses as compared to maternal animals nor
was there evidence of an increase in severity of effects at or below
maternally toxic doses following in utero exposure in the prenatal
developmental toxicity studies in rats and rabbits.
In the prenatal/postnatal 2-generation reproduction study
in rats, there was no evidence of enhanced susceptibility in pups when
compared to parental animals (i.e., effects noted in offspring occurred
at maternally toxic doses or higher).
There was no evidence of abnormalities in the development
of the fetal nervous system in the prenatal/postnatal studies submitted
to the Agency.
Adequate actual data, surrogate data, and/or modeling
outputs are available to satisfactorily assess food exposure and to
provide a screening level drinking water exposure assessment.
i. Acute dietary toxicity (females 13 years and older). The Agency
divided the NOAEL dose of 10 mg/kg/day from the rabbit developmental
study (MRID No. 44024949) by 300 (10 for individual variation x 10 for
species variation x 3 for lack of a developmental neurotoxicity study)
to calculate an acute population-adjusted dose (aPAD) of 0.033 mg/kg
for females 13 years or older.
ii. Acute dietary toxicity (general population and infants and
children). The Agency divided the LOAEL dose of 125 mg/kg from the
acute neurotoxicity study (MRID No. 44411317) by 300 (3 for lack of a
NOAEL x 10 for individual variation x 10 for species variation) to
calculate an aPAD of 0.42 mg/kg for the general population (300-fold
FQPA safety factor) and by dividing by an additional 3-fold FQPA safety
factor for lack of a developmental neurotoxicity study to calculate an
aPAD of 0.14 mg/kg for infants and children (900-fold safety factor).
iii. Chronic toxicity. EPA divided the NOAEL dose of 0.377 mg/kg/
day from a chronic feeding study in the rat (MRID No. 44024951) by 100
(10 for individual variation x 10 for species variation) to calculate a
chronic population-adjusted dose (cPAD) of 0.0038 mg/kg/day for the
general population by dividing by a additional 3-fold FQPA safety
factor to calculate a cPAD of 0.0013 mg/kg/day for females 13 years and
older and for infants and children.
C. Exposures and Risks
1. Proposed uses. Pymetrozine is a new insecticide of the pyridine
azomethine type. Pymetrozine is proposed for the control of aphids and
suppression of whiteflies in a variety of crops. The mode of action of
pymetrozine has not been precisely determined biochemically;
physiologically, it appears to act by preventing these insects from
inserting their stylus into the plant tissue.
Pymetrozine is proposed for use on tuberous and corm vegetables
(Subgroup 1-C) and tobacco under FulfillTM and ornamental
plants under RelayTM. Currently, there are no requested
homeowner applications for pymetrozine. However; post-application
(residential) exposure could occur due to contact with treated
ornamental plants. As both FulfillTM and RelayTM,
pymetrozine is formulated as a water-dispersible granule containing 50%
active ingredient.
FulfillTM may be applied by either ground or aerial
broadcast equipment, in a minimum of 10 gallons of water per acre;
chemigation is not permitted. Pymetrozine is applied to the foliage of
affected plants where it is quickly absorbed. Potato and tobacco crops
may be treated up to twice, each at a maximum rate of 0.09 pound (lb)
active ingredient per acre (ai/acre). The maximum seasonal use rate is
0.17 lb ai/acre. The retreatment and pre-harvest intervals are 7 and 14
days, respectively. The label for FulfillTM specifies a
restricted-entry interval of 12 hours.
RelayTM is to be broadcast-applied to ornamentals at a
rate not to exceed 10 oz./acre/application. Multiple applications may
be made on a 7- to 14-day interval. For indoor use, the yearly
application rate is not to exceed 100 oz./acre/year; for outdoor use,
the maximum rate is 48 oz./acre/year.
The above uses result in food and feed, drinking water, and non-
dietary (residential) exposures as outlined below (2-4).
2. From food and feed uses. This rule establishes the first
tolerance for pymetrozine.
Section 408(b)(2)(E) authorizes EPA to use available data and
information on the anticipated residue levels of pesticide residues in
food and the actual levels of pesticide chemicals that have been
measured in food. If EPA relies on such information, EPA must require
that data be provided 5 years after the tolerance is established,
modified, or left in effect, demonstrating that the levels in food are
not above the levels anticipated. Following the initial data
submission, EPA is authorized to require similar data on a time frame
it deems appropriate. As required by section 408(b)(2)(E), EPA will
issue a data call-in for information relating to anticipated residues
to be submitted no
[[Page 52445]]
later than 5 years from the date of issuance of this tolerance.
Section 408(b)(2)(F) states that the Agency may use data on the
actual percent of crop treated (PCT) for assessing chronic dietary risk
only if the Agency can make the following findings: That the data used
are reliable and provide a valid basis to show what percentage of the
food derived from such crop is likely to contain such pesticide
residue; that the exposure estimate does not underestimate exposure for
any significant subpopulation group; and if data are available on
pesticide use and food consumption in a particular area, the exposure
estimate does not understate exposure for the population in such area.
In addition, the Agency must provide for periodic evaluation of any
estimates used. To provide for the periodic evaluation of the estimate
of PCT as required by section 408(b)(2)(F), EPA may require registrants
to submit data on PCT.
Most of the dietary risk assessments performed on pymetrozine used
a Tier 1 approach for fruiting vegetables, cucurbits, and potatoes,
crops originally requested in the petition. That is, the Agency assumed
100% crop treated and tolerance level residues. For carcinogenicity
risk assessment, the Agency used a Tier 3 chronic dietary exposure
analysis for only tuberous and corm vegetables. This was based on 20%
of the crop treated and an anticipated residue of 0.0046 ppm to refine
the cancer risk. Novartis supplied this estimate of PCT to the Agency.
Based on the number of existing alternatives, the PCT could be much
lower. However, the market is looking for rotational alternatives to
prevent the buildup of resistance and to replace organophosphate (OP)
insecticides threatened by FQPA. The Agency reviewed Novartis' estimate
and found it reasonable.
The Agency believes that the three conditions, discussed in section
408 (b)(2)(F) in this unit concerning the Agency's responsibilities in
assessing chronic dietary risk findings, have been met. EPA finds that
the PCT information is reliable and has a valid basis. Before the
petitioner can increase production of product for treatment of greater
than 340,000 acres (20% of 1,700,000 total acres for the tuberous and
corm subgroup), permission from the Agency must be obtained. The
regional consumption information and consumption information for
significant subpopulations is taken into account through EPA's
computer-based model for evaluating the exposure of significant
subpopulations including several regional groups. Use of this
consumption information in EPA's risk assessment process ensures that
EPA's exposure estimate does not understate exposure for any
significant subpopulation group and allows the Agency to be reasonably
certain that no regional population is exposed to residue levels higher
than those estimated by the Agency. Other than the data available
through national food consumption surveys, EPA does not have available
information on the consumption of food in a particular area.
i. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a 1-day or single exposure.
The Tier 1 Dietary Exposure Evaluation Model (DEEMTM)
analysis indicates that acute dietary (food only) exposure to
pymetrozine from all in the original petition (tuberous and corm,
fruiting, and curcubits) will be below EPA's level of concern (100% of
the aPAD) and will not occupy more than 7% (of the aPAD for any
population subgroup, including those of infants and children. For the
maximum-exposed subgroup, the 95th percentile of exposure (children
ages 1-6 years) is predicted to be 3.3% of the aPAD. Due to
pymetrozine's lower acute endpoint for females 13-50 years (0.033 mg/
kg) versus that of other population subgroups (0.14 mg/kg), the
percentage of the aPAD occupied for females 13-50 years (6.5%) is
slightly higher than that estimated for children 1-6 years. For a Tier
1 analysis, EPA considers exposure at the 95th percentile of exposure.
Even at the 99.9th percentile of exposure, the acute risk is well below
EPA's level of concern.
ii. Chronic exposure and risk. The Tier 1 DEEMTM chronic
analysis indicates that exposure to pymetrozine from tuberous and corm
vegetables (Subgroup 1-C), cucurbits and fruiting vegetables will
occupy less than 74% of the cPAD for children ages 1-6 (the most highly
exposed population subgroup). Chronic dietary risk to all other
subgroups is less than that of children ages 1-6. See Table 1 below.
Table 1. Chronic Dietary (Food Only) Tier 1 Exposure and Risk Estimates for Pymetrozine Use
----------------------------------------------------------------------------------------------------------------
Population Subgroup cPAD, mg/kg/dayb Exposure, mg/kg/day % cPADc
----------------------------------------------------------------------------------------------------------------
U.S. Population (total)a............. 0.0038 0.000455 12
Hispanics............................ 0.0038 0.000496 13
Children 1-6 yrs..................... 0.0013 0.000958 74
Females 13-19 (not pregnant or 0.0013 000.480 37
nursing)............................
Males 13-19 yrs...................... 0.0038 0.000500 13
----------------------------------------------------------------------------------------------------------------
aPopulation subgroups shown include the U.S. general population and the maximally exposed subpopulation of
adults, infants and children, and women of child-bearing age.
bcPAD values incorporate the different FQPA Safety Factors for the various population subgroups.
c% cPAD = Exposure (mg/kg/day) cPAD (mg/kg/day) 100.
iii. Cancer exposure and risk. The Agency used a Tier 3
DEEMTM analysis for cancer risk estimates to the U.S.
population. Based on use of pymetrozine on tuberous and corm vegetables
only, the food only cancer risk is 1.7 10-7, which is below
the Agency's level of concern.
3. From drinking water. Pymetrozine is not persistent, breaking
down in the environment through a number of mechanisms and degradation
pathways including hydrolysis and aqueous and soil photolysis.
Laboratory studies indicate that pymetrozine is a ``low mobility'' to
``no mobility'' chemical with respect to leaching. The environmental
fate profile and application rates suggest that there should not be any
notable concerns in the areas of soil mobility and persistence for
pymetrozine resulting from its agriculture use to control aphids and
whiteflies. Based on the low application rate, the field dissipation
data, and the minimal concentrations relative to the parent (<10%, total),="" pymetrozine="" degradates="" should="" not="" enter="" ground="" and="" surface="" water="" to="" any="" appreciable="" extent.="" epa="" used="" the="" screening="" concentration="" in="" ground="" water="" (sci-grow)="" model="" to="" predict="" the="" [[page="" 52446]]="" environmental="" estimated="" concentrations="" (eecs)="" for="" pymetrozine="" in="" ground="" water.="" sci-grow="" is="" a="" regression="" model="" based="" on="" actual="" ground="" water="" monitoring="" data.="" sci-grow="" appears="" to="" provide="" realistic="" estimates="" of="" pesticide="" concentrations="" in="" shallow,="" highly="" vulnerable="" ground="" water="" sites.="" using="" the="" highest="" application="" rate="" of="" 0.187="" lb="" ai/acre="" (hops),="" sci-grow="" estimates="" the="" concentration="" of="" pymetrozine="" in="" ground="" water="" to="" be="" 0.015="">g/L. As there is relatively little temporal variation
in ground water, this estimate can be used for both acute and chronic
exposure scenarios.
In addition, EPA used the Tier 2 GENeric Estimated Environmental
Concentration (GENEEC) and Pesticide Root Zone Model-EXAMS (PRZM-EXAMS)
model to obtain Estimated Environmental Concentrations (EECs) in
surface water. The standard PRZM-EXAMS runoff modeling scenario is
based on a 10 ha field draining into a 1 ha by 2 meter deep small water
body. This scenario represents a watershed drainage area:water volume
ratio of 5 m2/m3. Each PRZM modeling scenario
represents a unique combination of climatic conditions (e.g.,
rainfall), crop specific management practices, soil specific
properties, site specific hydrology, and pesticide specific application
and dissipation processes. Each PRZM simulation is conducted for
multiple years to provide a probabilistic exposure characterization for
a single site. Based on 2 applications of pymetrozine on sweet potato,
each at 0.176 lb ai/acre, PRZM- EXAMS estimates acute (peak) EEC of
pymetrozine in surface water to be 1.85 g/L and estimates the
chronic (36-year mean) EEC of pymetrozine in surface water to be 0.222
g/L.
The EEC's for surface water (1.85 g/L and 0.222
g/L) are higher than those for ground water (0.015 g/
L). Therefore, surface water EEC's will be used to: (1) Estimate actual
concentrations of pymetrozine in water and (2) to compare those
conentrations with the Drinking Water Levels of Comparison (DWLOCs) in
g/L. DWLOCs are acceptable concentrations of pymetrozine in
drinking water as theoretical upper limits in light of total aggregate
exposure to that pesticide from food, water, and residential uses. EPA
calculates each DWLOC by subtracting the food and residential exposures
(if appropriate) from the PAD or Cancer Dose and by converting this
resulting dose, called the Maximum Water Exposure (in mg/kg/day), into
a concentration of pymetrozine in water expressed in g/L. Only
pymetrozine was included in the drinking water assessment on the basis
that the metabolites would not be found in drinking water.
Table 2 shows the DWLOC's for acute and chronic exposure.
Table 2. Drinking Water Levels of Comparison for Aggregated Exposures
--------------------------------------------------------------------------------------------------------------------------------------------------------
Population-Adjusted Maximum Water Exposure
Scenario/Population Subgroupa Dose, mg/kg/day Exposure mg/kg/dayb mg/kg/day DWLOC g/Lc
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acute Exposure [EEC=1.9]
U.S. Population..................................... 0.42 0.001980 0.418020 15000
Hispanic............................................ 0.42 0.002285 0.417715 15000
Children (1-6 yrs).................................. 0.14 0.004556 0.135444 1400
Females (13-19, not pregnant or nursing)............ 0.033 0.0021 39 0.030861 930
Males (13-19 yrs)................................... 0.42 0.002052 0.417948 15000
Short-termd Exposure
Toddlers............................................ 0.033 0.00097 0.032030 320
Chronic Exposure [EEC=0.22]
U.S. Population..................................... 0.0038 0.000455 0.003345 120
Hispanic............................................ 0.00380 0.000496 0.003304 120
Children (1-6 yrs).................................. 0.0013 0.000958 0.000342 3.4
Females (13-19, not pregnant or nursing)............ 0.0013 0.000480 0.000820 25
Males (13-19)....................................... 0.0038 0.000500 0.003300 120
--------------------------------------------------------------------------------------------------------------------------------------------------------
aPopulation subgroups shown include the U.S. general population and the maximally exposed subpopulation of adults, infants and children, and women of
child-bearing age for each exposure scenario.
bExposure is the sum of dietary and non-dietary exposure. For the case of pymetrozine, only the short-term and cancer DWLOC have a non-dietary
component. See Section 5.4 for clarification.
cDWLOC = Maximum Water Exposure (mg/kg/day) 1,000 g/mg body weight (70 kg general population/males 13+, 60 kg females 13+, 10 kg infants and
children) Water Consumption (2 L/day adults, 1 L/day infants and children). The acute EEC is 1.9 g/L, the chronic and cancer EEC is
0.22 g/L.
dFor short-term exposure, the short-term oral NOAEL was converted to a PAD by applying the 100x and 3x safety factors. Chronic food exposure for
children ages 1-6 was used to estimate background food exposure.
i. Acute exposure and risk. For acute aggregate exposure scenarios,
the DWLOC values (930-15,000 g/L) are all in excess of the
modeled acute EEC values (1.9 g/L); thus, drinking water is
not expected to be a significant contributor towards this type of
exposure.
ii. Chronic exposure and risk. For chronic (non-cancer) aggregate
exposure scenarios, the DWLOC values (3.4-120 g/L) are all in
excess of the modeled EEC values (0.22 g/L); thus, drinking
water is not expected to be a significant contributor towards this type
of exposure.
iii. Cancer exposure and risk. Preliminary analysis suggested that
drinking water may be a significant contributor towards cancer risk.
Therefore, the Agency did an aggregate quantitative risk assessment
which is discussed in section D3 of this unit.
4. From non-dietary exposure. As currently proposed, pymetrozine
could be used on the following residential non-food sites: ornamentals
(landscape, ground-covers, interiorscapes); home nurseries, non-bearing
orchards, and greenhouses. The end-use product, RelayTM, may
not be applied by homeowners, but post-application exposure could
occur. There are no intermediate-term exposure scenarios for which a
risk assessment is required. Short-term exposures are not applicable
for adults but are applicable for toddlers.
Since there was no chemical-specific data to determine dislodgeable
residues, EPA used its Standard Operating Procedures (SOPs) for
Residential
[[Page 52447]]
Exposure Assessment (Draft, December 18, 1997) to estimate post-
application exposure. This SOP does not include a scenario for
ornamentals, landscapes and groundcover. Therefore, this assessment
used the garden plants scenarios to determine post-application
exposures.
The post-application scenarios and associated Margins of Exposure
(MOEs) included: (1) Incidental non-dietary hand-to-mouth transfer of
pesticide residues (770,000) (2) incidental non-dietary ingestion of
pesticide-treated plants (not significant), and (3) incidental non-
dietary ingestion of soil from pesticide-treated areas (660,000). The
following assumptions were used for estimating post-application for the
three post-application scenarios.
Hand-to-mouth transfer (incidental non-dietary ingestion)
-Maximum application rate of 0.3125 lbs ai/A as specified on the
label
-20% of the application rate are available on the foliage as
dislodgeable residue
-Exposure is assessed on the same day the pesticide is applied
-Medium surface area of both hands is 350 cm2 for a
toddler (age 3 yrs)
-Mean rate of hand-to-mouth activity is 1.56 events/hr
-Duration of exposure was assumed to be 0.18 hrs/day (10 mins)
for toddlers
-A body weight of 15 kg was assumed for toddlers
-Short term NOAEL = 10 mg/kg/day (acute dietary)
-Hand-to-mouth exposure is not considered an intermediate-term
exposure scenario
Accidental Ingestion of Plant Material
-According to the HED SOP for Residential Exposure, exposure via
this route is considered negligible
Accidential Ingestion of Soil
-Maximum application rate of 0.3125 lbs ai per acre as specified
on the label
-20% of the application rate are available on the foliage as
dislodgeable residue
-Exposure is assessed on the same day the pesticide is applied
-The fraction of ai available in uppermost cm of soil is 1cm
-The assumed soil ingestion rate for children (ages 1-6 yrs) is
100 mg/day
-A body weight of 15 kg was assumed for toddlers
-Short term NOAEL = 10 mg/kg/day (acute dietary);
-Exposure from soil ingestion is not considered an intermediate-
term exposure scenario
These exposure estimates are based on upper-percentile (i.e.,
maximum application rate, available residues and duration of exposure)
and some central tendency (i.e., transfer coefficient, surface area,
hand-to-mouth activity, and body weight) assumptions and are considered
to be representative of high-end exposures. The uncertainties
associated with this assessment stem from the use of an assumed amount
of pesticide available from gardens, and assumptions regarding
dissipation, transfer of chemical residues, and hand-to-mouth activity.
The estimated exposures are believed to be reasonable high-end
estimates based on observations from chemical-specific field studies
and professional judgement.
EPA determined that the FQPA Safety Factor to protect infants and
children should be reduced to 3x and that the factor should apply to
female (13-50 years), infant, and children population subgroups for all
risk assessments. Thus, the levels of concern for these post-
application exposure scenarios are MOEs that are less than 100 for
adult populations and less than 300 for female (13-50), infant, and
children populations.
i. Chronic exposure and risk. Based on the proposed uses of
pymetrozine, EPA does not believe there will be chronic non-
occupational exposure to this insecticide.
ii. Cancer exposure and risk. EPA has estimated the lifetime
average daily dose for non-occupational exposure resulting from prining
and planting treated ornamental plants is 0.0000012 mg/kg/day.
A quantitative cancer risk assessment was performed for post-
application non-occupational exposure to treated ornamentals (e.g., a
home garden). Exposures were estimated using EPA's default activity
scenarios, transfer coefficients and input parameters as follows:
The fraction of active ingredient retained on foliage is
assumed to be 20% (0.2) on day zero (= percent dislodgeable foliar
residue, DFR, after initial treatment). This fraction is assumed to
further dissipate at the rate of 10% (0.1) per day on following days.
These are EPA's default values for exposure.
An application rate of 0.3125 lbs ai/acre (electrostatic
spray, pulsfog and low volume systems) was used to represent the worst
case scenario.
Transfer coefficient of 4,500 was used to represent
heaviest day of activity (planting, transplanting, and pruning) for
contact with treated ornamental plants.
Assumed homeowner worked 0.67 hours per day (Residential
SOP for Gardening).
Assumed homeowner worked a total of 2 days per year
performing heaviest activities (planting, pruning) at time points
shortly after pymetrozine application.
Assumed homeowner would be exposed for 50 years of their
life.
Dermal absorption = 1%.
Body weight = 70 kg.
Life expectance = 70 years.
Cancer Q* (mg/kg/day) = 2.05 x 10-1.
The cancer risk estimate for this post-application exposure is 2.4
x 10-7 and does not exceed EPA's level of concern (in the
range of 1 x 10-6) for the general population.
iii. Short- and intermediate-term exposure and risk. EPA did not
calculate MOEs for adults since there are no short-term dermal exposure
scenarios. However, short-term oral exposures and risks were calculated
for toddlers. For toddlers, the MOEs for short-term post-application
exposure scenarios are 770,000 and 660,000 for hand-to-mouth and soil
ingestion scenarios. These values are all greater than either of the
threshold values; thus, short-term risks are below the Agency's level
of concern.
4. Cumulative exposure to substances with a common mechanism of
toxicity. Section 408(b)(2)(D)(v) requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency
consider ``available information'' concerning the cumulative effects of
a particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.''
According to our information, there are no other pesticides that
have a common mechanism of toxicity with pymetrozine. Unlike other
pesticides for which EPA has followed a cumulative risk approach based
on a common mechanism of toxicity, pymetrozine does not appear to
produce a toxic metabolite produced by other substances. For the
purposes of this tolerance action, therefore, EPA has not assumed that
pymetrozine has a common mechanism of toxicity with other substances.
For information regarding EPA's efforts to determine which chemicals
have a common mechanism of toxicity and to evaluate the cumulative
effects of such chemicals, see the final rule for Bifenthrin Pesticide
Tolerances (62 FR 62961, November 26, 1997).
D. Aggregate Risks and Determination of Safety for U.S. Population
1. Acute risk. The risk from aggregate acute exposure from food and
drinking water from pymetrozine is below EPA's level of concern for the
following reasons. As indicated in Table 2, the Tier 1
DEEMTM analysis indicates that acute dietary (food only)
exposure to pymetrozine from fruiting vegetables, cucurbits, and
tuberous and corm
[[Page 52448]]
vegetables (Subgroup 1-C) will occupy less than 1/2% (0.001980/0.42) of
the aPAD for the U.S. Population, which is below EPA's level of concern
of 100% of the aPAD. In addition, for drinking water, the DWLOC value
(15000 g/L) for the U.S. Population is greatly in excess of
the modeled acute EEC value (1.9 g/L); thus, drinking water is
not expected to be a significant contributor towards this type of
exposure.
2. Chronic risk. As indicated in Table 1, the Tier 1
DEEMTM analysis indicates that chronic dietary (food only)
exposure to pymetrozine will utilize less than 12% (0.000455/0.0038) of
the cPAD for the U.S. population. EPA generally has no concern for
exposures below 100% of the cPAD because the cPAD represents the level
at or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health. In addition, for drinking
water, the DWLOC value (120 g/L) for the U.S. Population is
greatly in excess of the modeled EEC values (0.222 g/L); thus,
drinking water is not expected to be a significant contributor towards
this type of exposure. Despite the potential for exposure in the diet,
drinking water and from non-dietary, non-occupational exposure, EPA
does not expect the aggregate chronic exposure to exceed 100% of the
cPAD.
3. Aggregate cancer risk for U.S. population. For tuberous and corm
vegetables (Subgroup 1-C), EPA based its cancer risk assessment on a
Tier 3 estimate of dietary exposure, which incorporates anticipated
residues for pymetrozine and an estimate that 20% of the crops will be
treated. At this level of refinement, EPA's estimate of food exposure
and cancer risk were 0.0000008 mg/kg/day and 1.7 x10-7. EPA
also calculated a lifetime average daily dose of 0.0000012 mg/kg/day
for non-occupational exposure resulting from pruning and planting
treated ornamental plants.
EPA does not generally use surface water modeling values for
quantitative risk assessment. However, due to the statistical
uncertainties regarding the significance of cancer risks, which are
near 1 x 10-6, EPA has calculated the cancer risk resulting
from 0.22 g/L in drinking water to be 1.3 x 10-6.
The aggregate cancer risk is thus 1.7 x 10-6 (1.7 x
10-7 for food, 1.3 x 10-6, for water, and 2.4 x
10-7 for post-application residential exposure).
4. Determination of safety. EPA believes that the total risk
estimate for pymetrozine from food, drinking water, and residential
exposures of 1.7 x 10-6 generally represents a negligible
risk, as EPA has traditionally applied that concept. EPA has commonly
referred to a negligible risk as one that is in the range of 1 in 1
million (1 x 10-6). Quantitative cancer risk assessment is
not a precise science. There are a significant number of uncertainties
in both the toxicology used to derive the cancer potency of a substance
and in the data used to measure and calculate exposure. The Agency does
not attach great significance to numerical estimates for carcinogenic
risk that differ by less than a factor of 2. However, as a condition of
product registration, the Agency will require the registrant to submit
monitoring data. These data are expected to confirm that the actual
concentration of pymetrozine in drinking water is less than the level
of concern for all sub-populations and endpoints.
E. Aggregate Risks and Determination of Safety for Infants and Children
1. Safety factor for infants and children --i. In general. In
assessing the potential for additional sensitivity of infants and
children to residues of pymetrozine, EPA considered data from
developmental toxicity studies in rabbit, an acute neurotoxicity study
in the rat, and a chronic feeding study in the rat. See the
Toxicological Profile (section A. of this unit) for a discussion of
these tests.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for prenatal and postnatal toxicity and
the completeness of the data base unless EPA determines that a
different margin of safety will be safe for infants and children.
Margins of safety are incorporated into EPA risk assessments either
directly through use of a MOE analysis or through using uncertainty
(safety) factors in calculating a dose level that poses no appreciable
risk to humans. EPA believes that reliable data support using the
standard uncertainty factor (usually 100 for combined interspecies and
intraspecies variability) and the additional 3-fold MOE/uncertainty
factors, as described above, when EPA has a complete data base under
existing guidelines and when the severity of the effect in infants or
children or the potency or unusual toxic properties of a compound do
not raise concerns regarding the adequacy of these safety factors.
ii. Conclusion. EPA considered the available data and determined
that the 10-fold FQPA factor could be reduced to 3. A discussion of
these considerations may be found in B7 of this unit.
2. Acute risk. The risk from aggregate acute exposure from food and
drinking water from pymetrozine is below EPA level of concern for the
following reasons. The Tier 1 DEEMTM analysis indicates that
acute dietary (food only) exposure to pymetrozine from tuberous and
corm vegetables (Subgroup 1-C), fruiting vegetables and curcubits will
occupy less than 4% (0.004556/0.14) of the aPAD for children (1 to 6
years old), which is below EPA's level of concern of 100% of the aPAD.
In addition, for drinking water, the DWLOC value (1,400 g/L)
for children (1 to 6 years old) is greatly in excess of the modeled
acute EEC values (1.9 g/L); thus, drinking water is not
expected to be a significant contributor towards this type of exposure.
3. Chronic risk. Using the residue concentration exposure
assumptions described in this unit, the risk from aggregate chronic
exposure from food and drinking water from pymetrozine is below EPA's
level of concern for the following reasons. As indicated in the
previous table, the Tier 1 DEEMTM analysis indicates that
chronic dietary (food only) exposure to pymetrozine will utilize less
than 74% (0.000958/0.0013) of the cPAD for children (1 to 6 years old).
EPA generally has no concern for exposures below 100% of the cPAD
because the cPAD represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable risks to
human health. In addition, for drinking water, the DWLOC value (3.4
g/L) for children (1 to 6 years old) exceeds the modeled
chronic EEC values (0.222 g/L); thus, drinking water is not
expected to be a significant contributor towards this type of exposure.
Despite the potential for exposure in the diet, drinking water and from
non-dietary, non-occupational exposure, EPA does not expect the
aggregate chronic exposure to exceed 100% of the cPAD.
4. Short-term risk. In aggregating short-term risk, EPA considered
background average dietary exposure and short-term, non-dietary oral
exposure. Non-dietary oral exposure may occur as hand-to-mouth transfer
of residues from ornamental plants or incidental ingestion of
surrounding soil. The lowest short-term MOE value is for toddlers.
Combining this MOE (660,000) with that from dietary exposure (Short-
term oral NOAEL/chronic dietary exposure = 10/0.00096
10,000) results in an aggregate MOE of 10,000. As this
value is greater than 300, the short-term aggregate risk is below the
Agency's level of concern. Aggregated short-term exposure results in a
DWLOC of 320 g/L. This value is in excess of the peak EEC for
pymetrozine (1.9 g/L; see Table 2).
[[Page 52449]]
5. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty of no harm to infants
and children from aggregate exposure to pymetrozine residues.
IV. Other Considerations
A. Metabolism in Plants and Animals
Data concerning the metabolism of pymetrozine in plants and animals
have been previously submitted. The nature of residues in plants and
animals is adequately understood. The tolerance expression is for
pymetrozine per se. The residues of concern for risk assessment are
pymetrozine; the plant metabolites GS-23199 [6-methyl-1,2,4-triazin-3,5
(2H,4H)-dione], CGA-215525 [4-amino-4,5-dihydro-6-methyl-1,2,4-triazin-
3(2H)-one], CGA-249257 [4,5-dihydro-6-methyl-1,2,4-triazin-3(2H)-one],
CGA-294849 [4-amino-6-methyl-1,2,4-triazin- 3,5(2H,4H)-dione]; and the
ruminant metabolite CGA-313124 [4,5-dihydro-6-hydroxymethyl-4-[(3-
pyndynyl methylene)amino]-1,2,4-triazin-3(2H)-one] (free acid
conjugated).
B. Analytical Enforcement Methodology
Adequate enforcement methodology for pymetrozine (Novartis
Analytical Method AG-643) is currently being validated. Following
validation, it will be available to enforce the tolerance expression.
At that time the method may be requested from: Calvin Furlow, PIRIB,
IRSD (7502C), Office of Pesticide Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460; telephone number: (703)
305-5229; e-mail address: furlow.calvin@epa.gov..
C. Magnitude of Residues
The crop field trial data support the proposed tolerances for
residues of ``pymetrozine, per se.''
D. International Residue Limits
The are no established European (CODEX), Canadian, or Mexican
Maximum Residue Limits (MRLs) for pymetrozine. There are provisional
MRLs in Germany for hops (10 ppm) and potatoes (0.02 ppm). The European
Union is currently evaluating a proposed tolerance of 5 ppm on hops. At
this time, international harmonization of residue levels is not an
issue.
E. Rotational Crop Restrictions
The label has been revised to include only the following sites:
Tuberous and corm vegetables (Subgroup 1-C) and tobacco. The label also
includes a plant back restriction of not less than 120 days for all
leafy and root crops, and not less than 365 days for all other crops.
F. Pre-harvest Intervals
The pre-harvest interval for pymetrozine on the tuberous and corm
vegetables (Subgroup 1-C) is 14 days.
V. Conclusion
Therefore, the tolerance is established for residues of pymetrozine
per se in tuberous and corm vegetables (Subgroup 1-C), at 0.02 ppm.
VI. Objections and Hearing Requests
Under section 408(g) of the FFDCA, as amended by the FQPA, any
person may file an objection to any aspect of this regulation and may
also request a hearing on those objections. EPA procedural regulations
which govern the submission of objections and requests for hearings
appear in 40 CFR part 178. Although the procedures in those regulations
require some modification to reflect the amendments made to the FFDCA
by the FQPA of 1996, EPA will continue to use those procedures, with
appropriate adjustments, until the necessary modifications can be made.
The new section 408(g) provides essentially the same process for
persons to ``object'' to a regulation for an exemption from the
requirement of a tolerance issued by EPA under new section 408(d), as
was provided in the old FFDCA sections 408 and 409. However, the period
for filing objections is now 60 days, rather than 30 days.
A. What Do I Need to Do to File an Objection or Request a Hearing?
You must file your objection or request a hearing on this
regulation in accordance with the instructions provided in this unit
and in 40 CFR part 178. To ensure proper receipt by EPA, you must
identify docket control number OPP-300929 in the subject line on the
first page of your submission. All requests must be in writing, and
must be mailed or delivered to the Hearing Clerk on or before November
29, 1999.
1. Filing the request. Your objection must specify the specific
provisions in the regulation that you object to, and the grounds for
the objections (40 CFR 178.25). If a hearing is requested, the
objections must include a statement of the factual issues(s) on which a
hearing is requested, the requestor's contentions on such issues, and a
summary of any evidence relied upon by the objector (40 CFR 178.27).
Information submitted in connection with an objection or hearing
request may be claimed confidential by marking any part or all of that
information as CBI. Information so marked will not be disclosed except
in accordance with procedures set forth in 40 CFR part 2. A copy of the
information that does not contain CBI must be submitted for inclusion
in the public record. Information not marked confidential may be
disclosed publicly by EPA without prior notice.
Mail your written request to: Office of the Hearing Clerk (1900),
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
You may also deliver your request to the Office of the Hearing Clerk in
Rm. M3708, Waterside Mall, 401 M St., SW., Washington, DC 20460. The
Office of the Hearing Clerk is open from 8 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays. The telephone number for the
Office of the Hearing Clerk is (202) 260-4865.
2. Tolerance fee payment. If you file an objection or request a
hearing, you must also pay the fee prescribed by 40 CFR 180.33(i) or
request a waiver of that fee pursuant to 40 CFR 180.33(m). You must
mail the fee to: EPA Headquarters Accounting Operations Branch, Office
of Pesticide Programs, P.O. Box 360277M, Pittsburgh, PA 15251. Please
identify the fee submission by labeling it ``Tolerance Petition Fees.''
EPA is authorized to waive any fee requirement ``when in the
judgement of the Administrator such a waiver or refund is equitable and
not contrary to the purpose of this subsection.'' For additional
information regarding the waiver of these fees, you may contact James
Tompkins by phone at (703) 305-5697, by e-mail at tompkins.jim@epa.gov,
or by mailing a request for information to Mr. Tompkins at Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460.
If you would like to request a waiver of the tolerance objection
fees, you must mail your request for such a waiver to: James Hollins,
Information Resources and Services Division (7502C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460.
3. Copies for the Docket. In addition to filing an objection or
hearing request with the Hearing Clerk as described in Unit VI.A. of
this preamble, you should also send a copy of your request to the PIRIB
for its inclusion in the official record that is described in Unit
I.B.2. of this preamble. Mail your copies, identified by docket number
OPP-300929, to: Public Information and Records Integrity Branch,
Information Resources and Services Division (7502C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In
[[Page 52450]]
person or by courier, bring a copy to the location of the PIRIB
described in Unit I.B.2. of this preamble. You may also send an
electronic copy of your request via e-mail to: opp-docket@epa.gov.
Please use an ASCII file format and avoid the use of special characters
and any form of encryption. Copies of electronic objections and hearing
requests will also be accepted on disks in WordPerfect 6.1/8.0 file
format or ASCII file format. Do not include any CBI in your electronic
copy. You may also submit an electronic copy of your request at many
Federal Depository Libraries.
B. When Will the Agency Grant a Request for a Hearing?
A request for a hearing will be granted if the Administrator
determines that the material submitted shows the following: There is a
genuine and substantial issue of fact; there is a reasonable
possibility that available evidence identified by the requestor would,
if established resolve one or more of such issues in favor of the
requestor, taking into account uncontested claims or facts to the
contrary; and resolution of the factual issues(s) in the manner sought
by the requestor would be adequate to justify the action requested (40
CFR 178.32).
VII. Regulatory Assessment Requirements
This final rule establishes a tolerance under section 408(d) of the
FFDCA in response to a petition submitted to the Agency. The Office of
Management and Budget (OMB) has exempted these types of actions from
review under Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993). This final rule does not contain
any information collections subject to OMB approval under the Paperwork
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable
duty or contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act of 1995 (UMRA) (Public Law 104-4). Nor
does it require prior consultation with State, local, and tribal
government officials as specified by Executive Order 12875, entitled
Enhancing the Intergovernmental Partnership (58 FR 58093, October 28,
1993) and Executive Order 13084, entitled Consultation and Coordination
with Indian Tribal Governments (63 FR 27655, May 19,1998), or special
consideration of environmental justice related issues under Executive
Order 12898, entitled Federal Actions to Address Environmental Justice
in Minority Populations and Low-Income Populations (59 FR 7629,
February 16, 1994) or require OMB review in accordance with Executive
Order 13045, entitled Protection of Children from Environmental Health
Risks and Safety Risks (62 FR 19885, April 23, 1997). The Agency has
determined that this action will not have a substantial direct effect
on States, on the relationship between the national government and the
States, or on the distribution of power and responsibilities among the
various levels of government, as specified in Executive Order 12612,
entitled Federalism (52 FR 41685, October 30, 1987). This action
directly regulates growers, food processors, food handlers and food
retailers, not States. This action does not alter the relationships or
distribution of power and responsibilities established by Congress in
the preemption provisions of the Federal Food, Drug, and Cosmetic Act,
21 U.S.C. 346a(b)(4). This action does not involve any technical
standards that would require Agency consideration of voluntary
consensus standards pursuant to section 12(d) of the National
Technology Transfer and Advancement Act of 1995 (NTTAA), Public Law
104-113, section 12(d) (15 U.S.C. 272 note). In addition, since
tolerances and exemptions that are established on the basis of a
petition under FFDCA section 408(d), such as the tolerance in this
final rule, do not require the issuance of a proposed rule, the
requirements of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et
seq.) do not apply.
VIII. Submission to Congress and the Comptroller General
The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General of the
United States. EPA will submit a report containing this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of this rule in the Federal Register. This rule is not
a ``major rule'' as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: September 23, 1999.
Susan B. Hazen,
Acting Director, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180--[AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 321(q), (346a) and 371.
2. Section 180.556 is added to read as follows:
Sec. 180.556 Pymetrozine; tolerances for residues.
(a) General. Tolerances are established for residues of the
insecticide pymetrozine [1,2,4-triazin-3(2H)-one,4,5-dihydro-6-methyl-
4-[(3- pyridinylmethylene) amino]] in or on the following raw
agricultural commodities. The tolerance level for each commodity is
expressed in terms of the parent insecticide only, which serves as an
indicator or the use of pymetrozine on these raw agricultural
commodities.
------------------------------------------------------------------------
Expiration/
Commodity Parts per million Revocation Date
------------------------------------------------------------------------
Corm and Tuberous Vegetables 0.02 None
Subgroup 1-C.
------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
[FR Doc. 99-25313 Filed 9-28-99; 8:45 am]
BILLING CODE 6560-50-F
